A population of T lymphocytes known as NK T cells recognizes specific lipid ligands in the context of MHC class I-like CD1d molecules and has recently been found to contribute to the regulation of immune responses and the maintenance of immunological tolerance to self antigens. Numerous published reports have linked the loss of NK T cells and changes in their function to the progression of autoimmune diseases, including systemic lupus erythematosus (SLE) and mouse models of this disease. The central hypothesis of the current proposal is that NK T cells constitute an important regulatory arm of the immune system that normally assists in preventing the development of aggressive autoimmunity such as that which occurs in full-blown SLE. The proposed studies will evaluate changes in NK T cells during the progression of spontaneous lupus-like disease in NZB/W F1 mice, and will determine the influence of NK T cells on SLE-associated autoantibody production in murine models of spontaneous and induced SLE-like disease. These studies will build on preliminary findings that strongly implicate NK T cells as a major factor in the regulation of marginal zone B cells, a distinct B cell subset with inherent autoreactivity that has recently become a significant focus for research into the origins of autoantibody production in SLE. Methods that should allow the direct stimulation of NK cells in vivo will be investigated as potential approaches to therapy of SLE that could take advantage of the natural functions of these regulatory T cells. The program project format provides an optimal environment for these studies by providing numerous collaborative interactions with the other members of the program who bring it a wealth of expertise and resources for the analysis of murine models of SLE that are highly relevant to this proposal. These studies will also benefit from extensive usage of all of the Program's proposed core facilities.